Project Summary/Abstract Dr. Gavin Ha is a postdoctoral research fellow in the laboratory of Dr. Matthew Meyerson at Dana-Farber Cancer Institute and the Broad Institute of MIT & Harvard. His long-term career goal, in alignment with the mission of the NCI, is to reduce cancer-associated mortality by determining the mechanisms driving cancer progression and treatment resistance, developing cancer diagnostics, and identifying candidate therapeutic targets. To accomplish this goal, Dr. Ha will integrate computational biology, genomics, and molecular biology approaches to study advanced cancers from both tumor and liquid biopsies. Late-stage advanced cancers lead to the majority of cancer-related deaths. Metastatic castration-resistant prostate cancer (mCRPC) is an example of a disease that is lethal with no curative treatment. There are few whole genome studies of mCRPC because tumors are often less accessible. Recently, Dr. Ha and others have discovered alterations of DNA enhancer elements driving the expression of oncogenes. Thus, there is an urgent need for deeper analysis of cancer genomes, beyond coding regions, to uncover new non-coding alterations driving cancer progression. This proposal will address these challenges by building the necessary analytical tools to characterize the whole genomes of metastatic cancers from both tumor and liquid biopsies. In Aim 1, Dr. Ha will develop novel computational approaches to analyze linked-read sequencing, a new technology that provides long-range genomic data, to more accurately characterize alterations in tumor genomes. In Aim 2, he will use cell-free DNA from patient blood as a means to non-invasively access large cohorts of patients to detect tumor-specific alterations. Then, in Aim 3, he will analyze both tumor and cell-free DNA to identify non-coding genomic alterations affecting regulatory elements in mCRPC patients. He will perform longitudinal analysis from blood samples collected during treatment to identify alterations that may be implicated in resistance. These proposed projects will create much-needed analytical methods for emerging technologies to analyze tumor and cell-free DNA and will provide insights into the mechanisms underpinning treatment resistance in mCRPC. The K22 award will allow Dr. Ha to further enhance his ability to perform cutting-edge cancer research by acquiring knowledge in techniques of molecular biology through scientific collaborations. The proposed development plan will enable him to become a well-rounded independent investigator and to prepare him to lead a multi-disciplinary group with expertise in computational and experimental aspects of cancer research. Dr. Ha has access to an outstanding research environment, state-of-the-art facilities, and high-performance computing at the Dana-Farber Cancer Institute and the Broad Institute. Dr. Ha is expecting to obtain an independent position at a research institution with the same world-class facilities and intellectual environment.